6-halo-6-dehydro-a-norprogesterones



United States Patent 3,542,811 6-HALO-G-DEHYDRO-A-NORPROGESTERONESPatrick A. Diassi, Westfield, N.J., assiguor to E. R. Squibb & Sons,Inc., New York, N.Y., a corporation of Delaware N0 Drawing.Continuation-impart of application Ser. No. 370,113, May 25, 1964. Thisapplication Oct. 19, 1967, Ser. No. 676,628

Int. Cl. C07d 21/00 US. Cl. 260-3405 Claims ABSTRACT OF THE DISCLOSUREThis invention relates to 6-halo-6-dehydro-A-norprogesterones. Thesecompounds are physiologically active materials, possessingprogestatioanl activity. In addition, these compounds are useful assun-screening, anti-oxidant and anti-corrosive agents. They are alsosurfactants, and thus may be employed as emulsifiers and wetting agents.

wherein X is hydrogen or halo (e.g., chloro, bromo or fiuoro); R and Rare each hydrogen; and together R and R is wherein P is hydrogen, loweralkyl, halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyllower alkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclicheterocyclic or monocyclic heterocyclic lower alkyl; Q is lower alkyl,halo lower alkyl, monocyclic cycloalkyl, monocyclic cycloalkyl loweralkyl, monocyclic aryl, monocyclic aryl lower alkyl, monocyclicheterocyclic or monocyclic heterocyclic lower alkyl; or together withthe carbon to which they are joined P and Q is monocyclic cycloalkyl ormonocyclic heterocyclic.

The term lower alkyl, as employed herein, includes both straight andbranched chain radicals of less than eight carbon atoms. All fourhalogens are contemplated.

The term monocyclic aryl radicals contemplates monocyclic carbocyclicaryl radicals, for instance, phenyl and substituted phenyl radicals suchas lower alkylphenyl, e.g., 0-, m-, or p-tolyl-ethylphenyl; di-loweralkylphenyl, e.g., p-xylyl; lower alkoxyphenyl, e.g., methoxyphenyl;halophenyl, e. g., chlorophenyl, bromophenyl, etc.

The term monocyclic cycloalkyl includes cycloalkyl radicals containingfrom 3 to 6 ring members (e.g., cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl).

The term monocyclic heterocyclic includes heterocyclic radicalscontaining 5 or 6 ring members (e.g., furyl, thienyl, thiophenyl,thenyl, furfuryl, pyridyl, piperidinyl, morpholinyl, and the like).

The final products of this invention are physiologically activesubstances which possess progestational activity both orally andparenterally. As such they may be employed in the veterinary field fortreating conditions in both large and small animals (e.g., dogs, cats,sheep, cows, horses and the like) which require a progestational agent.For instance, in animal breeding, the compounds of this invention areuseful in preventing threatened abortion and may be administered forthis purpose in dosages of ,about 2 to about mg./kg. of body weightdaily. In addition, control of milk and egg production may be achievedby regulation of the cycles of cows and chickens through theadministration of the compounds of this invention in daily dosages, alsoof about 2 to about 100 mgjkg. of body weight.

Perorally acceptable formulations can be prepared in the usual manner toprovide an aqueous suspension, an elixir or a solid dosage unit form(e.g., tablet, powder or capsule), for example, two-piece hard gelatincapsules may be filled with a mixture of the active ingredient andexcipients (e.g., starch, talc, stearic acid, and/or magnesiumstearate). Also one piece gelatin capsules contain ing the same amountof medicament may be prepared using sufficient corn oil or othersuitable vegetable oil, to render the compound capsulatable. Tablets maybe prepared by using starch, lactose of other conventional excipients,and may be scored to enable the administration of fractional dosages, ifdesired. Any of the tableting material used in pharmaceutical practicemay be employed. Liquid preparations may be in the form of suspensions,emulsions, syrups or elixirs of the active substance in water or otherliquid medium commonly used for making orally acceptable pharmaceuticalformulations, such as liquid paraffin, or a syrup elixir base.

The active substance may also be made up in a form suitable forparenteral administration, i.e., as a suspension in sterile water or anorganic liquid usually employed for injectionable preparations, forexample a vegetable oil such as olive oil, or a sterile solution in anorganic solvent.

In addition, the compounds of this invention are surface active agentswhich may therefore be employed in a variety of applications requiringsuch an agent. For example, the compounds of this invention maybe employed as emulsifying agents in the preparation of lubricants,adhesives, polishes, wax com ositions, and the like. Further, thesecompounds are ultraviolet-absorbing materials and may be employed assun-screening agents. They may also be employed as antioxidants andcorrosion inhibitors for various hydrocarbons and mixtures thereof. Asexamples of materials to which the compounds of this invention may beadded for this purpose may be mentioned gasoline, hydrocarbonlubrication oils and greases, hydrocarbon solvents (e.g., toluene,kerosene) and the like.

The final products of this invention may be prepared according toprocesses of this invention, beginning with compounds of the formulawherein R and R are as defined hereinbefore and can be taken together toform wherein P and Q are as hereinbefore defined, as starting material.These starting materials utilizable in this invention may be preparedaccording to the procedures and teachings set forth in U.S. Pat. No.3,225,064, the disclosure of which also provides additionalexemplification of the terms P and Q.

The starting materials are first dehydrogenated as by treatment with adehydrogenating agent such as 2,3- dichloro-S,6-dicyanobenzoquinone in amineral acid, e.g., hydrogen chloride medium to yield the 6-dehydroderivatives of the starting materials.

The 6-dehydro derivatives are then oxidized as by treatment with aperbenzoic acid, for example, m-chloroperbenzoic acid to yield the6a,7a-oxido derivatives thereof.

The 60,7ot-OXidO compounds may then be reacted with an excess of ahydrohalide (e.g., hydrogen chloride or hydrogen bromide) at roomtemperature to yield the 6-halo-6-dehydro new final products of thisinvention.

Alternatively, the 6u,7u-oxido compounds may first be treated with 1molar equivalent of a hydrohalide, such as hydrogen chloride, underreduced temperatures, to yield the 6-halo-7-hydroxy derivatives of thisinvention, which are also new compounds thereof.

These 6-halo-7-hydroxy derivatives may then be treated with an excess ofhydrohalide, e.g., hydrogen chloride, at an elevated temperature toyield the 6-halo- 6-dehydro final products of this invention.

If a ketal or acetal group other than that present in the startingmaterial or final product or intermediates therefor is desired, therespective compound may be cleaved by treatment with aqueous formic acidto yield the respective free 16u,17a-dihydroxy compounds. These freediols may then be reacted with an aldehyde or ketone of the formulawherein P and Q are as hereinbefore defined, in order to yield thedesired 16,17-acetal or ketal derivatives. The reaction is preferablycarried out by treating a suspension or solution of the 16,17-dihydroxysteroid in the aldehyde or ketone, with an acid catalyst, for example,perchloric acid, neutralizing the acid and recovering the acetal orketal derivatives formed. Suitable aldehyde and ketone reactants includethose set forth in U.S. Pat. 3,077,471, issued Feb. 12, 1963.

The invention may be further illustrated by the following examples:

EXAMPLE 1 v 6-dehydro-l6u,17a-dimethylmethylenedioxy-A- norprogesteroneTo a solution of 2.0 g. of16oz,l7ot-dirnethylmethylenedioxy-A-norprogesterone in 100 ml. ofpurified dioxane, 1.25 g. of 2,3 -dichloro-5,6-dicyanobenzoquinone areadded and hydrogen chloride gas is bubbled through the resultingsolution for five minutes. The mixture is then stirred at roomtemperature for 18 hours during which time2,3-dichloro-5,6-dicyanohydroquinone precipitates. The mixture isfiltered, washed with benzene and the combined filtrate and washingsevaporated to dryness, in vacuo. The residue is redissolved in a smallvolume of benzene and adsorbed onto Woelm neutral alumina (Ac tivity I).Elution with chloroform and evaporation of the solvent gives 1.8 g. ofresidue which is redissolved in 40 ml. of collidine and refluxed for onehour. After cooling the mixture is diluted with chloroform and washedsuccessively with 2 N hydrochloric acid, 5% NaHCO and water untilneutral and then evaporated to dryness, in vacuo. The residue isredissolved in benzene and plate chromatographed using Woelm neutralalumina (Activity V) as adsorbant and benzene as the developing solvent.Detection of the band at R) 0.5 by U.V. and elution with ethyl acetategives material on evaporation of the solvent, in vacuo, which could becrystallized from acetone-hexane yielding 1.2 g. of6-dehydro-16a,17adimethylmethylenedioxy A norprogesterone having amelting point of about 213-215, [a] +36 (chloroform),

mg, 276 mp. $22,500

Analysfs.Calcd. for C H O (370.47) (percent): C, 74.56; H, 8.16. Found(percent): C, 74.64; H, 8.10.

EXAMPLE 2 6-dehydro-16a,17u- B-methyl-u-phenylmethylenedioxy)-A-nor-progesterone Following the procedure of Example 1 butsubstituting 16w17a-(B-methyl-u-phenylmethylenedioxy) A nor progesteronefor the 160:,17a dimethylmethylenedioxy- A-norprogesterone there isobtained 6-dehydro-l6a,l7a- (fl-methyl aphenylmethylenedioxy)-A-norprogesterone.

EXAMPLE 3 611,7oc-oxido-l6a,17ot-dimethylmethylenedioxy-A-norprogesterone A solution of1.0 g. of 6-dehydro-16a,17x-dimethylmethylenedioxy-A-norprogesterone inml. of methylenechloride is cooled to 0 and 2.25 g. ofmetachloroperbenzoic acid are added slowly with stirring. The reactionis kept at 0 C. for /2 hour and then at room temperature for 16 hours.It is then washed successively with 100 ml. portions of 5% sodiumbicarbonate, 5% sodium sulfite and water until neutral, dried oversodium sulfate and evaporated to dryness, in vacuo. Crystallization ofthe residue from acetone-hexane gives 830 mg. of 6a,7aoxido l6a,l7ocdimethylmethylenedioxy A-nor-progesterone having a melting point of240-242 C.

EXAMPLE 4 6a,7u-oxido-16a, 17 as-methyl-a-phenylmethylenedioxy)-A-norprogesterone Following the procedure of Example 3 but substituting6-d6hyd10-l6oc,l7a S-methyl 0c phenylmethylenedioxy)-A-norprogesteronefor the 6-dehydro 16a,17u-dimethylmethylenedioxy A-norprogesterone thereis obtained 6a,7a-oxido-16u,17m 3 methyl-a-phenylmethylenedioxy)-A-norprogesterone.

EXAMPLE 5 6 3-ch1oro-7 a-hydroxy-16u,17 u-dirnethylmethylenedioxy)-A-norprogesterone To a cold solution of 193 mg. of6a,7a-oxido-l6a,17adimethylmethylenedioxy A norprogesterone in 10 ml. ofchloroform is added 1.0 ml. of a solution containing 20 mg. of hydrogenchloride per ml. of chloroform. The solution is kept in an ice bath for2%. hours and then diluted with water. The chloroform is separated,washed with water until neutral and then evaporated to dryness. Theresidue is crystallized from acetone-hexane to give GB-ChlOIO-7oahydroxy 16a,17a dimethylmethylenedi oxy-A-norprogesterone.

EXAMPLE 6 6B-chloro-7m-hydroxy-16oz,17u- (fi-methyl-aphenylmethylenedioxy)-A-norprogesterone Following the procedure ofExample 5 but substituting 60:,70: oxido :,170:(fi-methyl-u-phenylmethylenedioxy) -A-noprogesterone for the 6u,7aOXidO-lGoz,

17w dimethylmethylenedioxy A norprogesterone there is obtainedGB-ChlOIO-7u-hYdlOXY 16a,l7a-(;8-methyl-uphenylmethylenedioxy)-Anorprogesterone.

EXAMPLE 7 6fl-bromo-7a-hydroxy 1604,1704dimethylmethylenedioxy-A-norprogesterone and 6fi-bromo 70c hydroxy-16u,17a (B methyl-ot-phenylmethylenedioxy)-A-norprogesterone Followingthe procedures of Examples 5 and 6 but substituting acetic acid forchloroform and hydrogen bromide in acetic acid for the hydrogen chloridein chloroform there are obtained6,8-bromo-h-hydroxydimethylmethylenedioxy-A norprogesterone and6fi-bromo-7ahydroxy 1604,1704 (fi-methyl-a-phenylmethylenedioxy)-A-norprogesterone.

EXAMPLE 8 6-chl oro-6-dehydro-l 6 c, 17 tat-dimethylmethylenedioxy-A-norprogesterone A solution of 200 mg.6a,7u-oxido-16a,Not-dimethylmethylenedioxy A norprogesterone in 10 ml.of chloroform is saturated at 0 C. with hydrogen chloride gas, thenstoppered and kept at 45 C. for 20 hours. The solution is then dilutedwith chloroform washed successively with sodium bicarbonate and thenWater, until neutral, and dried over sodium sulfate and evaporated todryness. Plate chromatography of the residue using Woelm neutral alumina(Activity V) as adsorbant, and benzene as developing solvent gives aband at Rf 0.5 detectable by ultraviolet and eluted with ethyl acetatewhich on evaporation of the solvent and crystallization of the residuefrom acetone-hexane gives 6-chloro-6-dehydro16a,17tat-dimethylmethylenedioxy A norprogesterone having a meltingpoint of 19l-193 C.,

[ab-{-13 (chloroform),

Analysis.--Calcd. for C H O Cl (404.94) (percent): C, 68.21; H, 7.22;Cl, 8.75. Found (percent): C, 68.15; H, 7.15; Cl, 8.97.

EXAMPLE 9 6-ch1oro-6-dehydro-16a,l7a-dimethylmethylenedioxy-A-norprogesterone Following the procedure of Example 8 but substituting66 chloro 70c hydroxy IMAM-dimethylmethylenedioxy-A-norprogesterone forthe 600,70: oxide-1611,17- dimethylmethylenedioxy-A-norprogesteronc,there is obtained 6-chloro-6-dehydro-16a,17adimethylmethylenedoxy-A-norprogesterone.

EXAMPLE 6-chloro-6-dehydro-16a,170t-(,B-methyl-u-phenylmethylenedioxy)-A-norprogesterone Following the procedure of Example 8 but substituting6a,7a-oxido l6a,l7u (B methyl-a-phenylmethylene dioxy)-A-norprogesteronefor the 6a,7o-OXid0-16oc,17udimethylmethylenedioxy A norprogesterone or613- chloro 7oz hydroxy16a,17a-(,3-methyl-a-phenylmethylenedioxy)-A-norprogesterone for the 6Bchloro-7mhydroxy 160:,170; dimethylmethylenedioxy-A-norprogesteronethere is obtained 6-chloro-6-dehydro-160:,17a- (/3methyl-a-phenylmethylenedioxy) A-norprogesterone.

EXAMPLE 11 6 bromo 6 dehydro 1611,1711 dimethylmethylenedioxy Anorprogesterone and 6 bromo 6-dehydro- 16a,17a (r3 methyl aphenylmethylenedioxy) A norprogesterone Following the procedures ofExamples 8 and 9 but substituting hydrogen bromide in acetic acid forthe hydrogen chloride in chloroform there are obtained 6- bromo 6dehydro-16a,17a-dimethylmethylenedioxy-A- norprogesterone and 6 bromo 6dehydro 16a,17a- (fi methyl u phenylmethylenedioxy) A norprogesterone.

EXAMPLE 12 6-dehydro-1604, 17a-dihydroxy-A-norprogesterone A solution of50 mg. of 6-delhydro-16a,l7a-dimethylmethylene dioxy A norprogesteronein 5 ml. of formic acid is heated on a steam bath for forty minutes andthen evaporated to dryness, in vacuo. The residue is then dissolved in10 ml. of methanol and 3 ml. of 10% potassium carbonate and stirred atroom temperature for /2 hour. It is then neutralized with dilute aceticacid, diluted with water and extracted with chloroform. The chloroformis Washed with water and evaporated to dryness in vacuo. Crystallizationof the residue gives 6-dehydro-16a,17a-dihydro-Amorprogesterone.

EXAMPLE l3 6 chloro 6 dehydro 16a,17w dihydroxy A norprogesterone and 6bromo 6 dehydro 16a,17otdihydroxy A norprogesterone EXAMPLE 14 6 dehydro160:,170: dimethylmethylenedioxy A- norprogesterone A solution of 50 mg.of 6-dehydro-l6u,17a-dihydroxy- A-norprogesterone in 10 ml. of acetonecontaining 0.01 ml. of perchloric acid is kept at room temperature fortwo hours. It is then neutralized with 5% sodium bicarbonate, dilutedwith Water and extracted with chloroform. The chloroform is washed withwater and evaporated to dryness, in vacuo. Crystallization of theresidue from acetone-hexane gives6-dihydro-l6a,17a-dimetl1ylmethylenedioxy-A-norprogesterone.

EXAMPLE 15 6 chloro 6 dehydro :,1711 dimethylmethylenedi oxy Anorprogesterone and 6 bromo 6 dehydro- 16a,17a dimethylmethylenedioxy Anorprogesterone Following the procedure of Example 14 but substituting 6bromoor 6 chloro 6 dehydro 160:,170; dihydroxy A norprogesterone for the6-dehydro-16a,l7adihydroxy-A-norproge-sterone, there is obtainedrespectively 6 bromo 6 dehydro 16a,17a dimethylmethylenedioxy Anorprogesterone and 6 chloro 6 dehydro 1604,17 dimethylmethylenedioxy Anorprogesterone.

What is claimed is:

1. A compound having the formula wherein X is halo, and R and R takentogether is Q wherein P is selected from the group consisting ofhydrogen, lower alkyl, halo lower alkyl, monocyclic cyc1o alkyl,monocyclic cycloalkyl-lower alkyl, monocyclic aryl, monocyclicaryl-lower alkyl; Q is selected from the group consisting of loweralkyl, halo lower alkyl, monocyclic cycloalkyl, monocycliccycloalkyl-lower alkyl, monocyclic aryl, monocyclic aryl-lower alkyl;and P and Q, taken together with the carbon to which they are joined, ismonocyclic cycloalkyl, wherein lower alkyl contains less than eightcarbon atoms, monocyclic cycloalkyl contains from 3 to 6 ring membersand the monocyclic aryl radicals is selected from the group consistingof phenyl, lower alkyl phenyl, di-lower alkyl phenyl, lower alkoxyphenyl and halophenyl.

2. A compound in accordance with claim 1 having the name 6-chloro 6dehydro-16a,17a-dimethylmethylenedioXy-A-norprogesterone.

3. A compound in accordance with claim 1 having the References CitedUNITED STATES PATENTS 3,213,142 10/1965 Weisenborn 260-586 3,225,06412/1965 Weisenborn 260304.5

ALEX MAZEL, Primary Examiner J. H. TURNIPSEED, Assistant Examiner US.Cl. X.R.

